Nucleophilic Substitutions at Aliphatic Carbon

Abstract

This chapter deals with enantioselective organocatalytic nucleophilic substitutions at aliphatic carbon, such as α-halogenations of carbonyl compounds, α-alkylations of carbonyl compounds and derivatives, α-aminations of carbonyl compounds, and miscellaneous reactions. The enantioselective organocatalytic synthesis of halogenated products represents an interesting synthetic challenge since their functionality serves as a lynchpin for further transformations. In this context, a powerful extension of the MacMillan enantioselective α-fluorination of aldehydes was developed on the basis of the treatment of an aldehyde with NFSI in the presence of a chiral imidazolidinone as organocatalyst, providing the corresponding intermediate α-fluoroaldehyde, which was subsequently submitted to a reductive amination, yielding the final β-fluoroamine in high enantioselectivity. Examples of organocatalytic synthesis of chiral α-iodoaldehydes are especially scarce, probably due to their ease of undesired racemisation. In an effort to address this issue, a novel bifunctional organocatalyst, consisting in a binaphthyl-based amine moiety and hydroxyl groups, was applied to the iodination of aldehydes with N-iodosuccinimide, yielding the corresponding α-iodoaldehydes in excellent enantioselectivities. Highly enantioselective alkylations of carbonyl compounds were developed under phase-transfer conditions. As an example, the use of a (S)-binaphthyl phase-transfer catalyst for the alkylation of N-diphenylmethylene glycine tert-butyl ester with a wide range of alkyl halides yielded the corresponding alkylated products in excellent general enantioselectivities by using an exceptional low catalyst loading of 0.01-0.05 mol %.